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www.thelancet.com/oncology Published online September 3, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00188-6
1
Articles
Lancet Oncol 2015
Published Online
September 3, 2015
http://dx.doi.org/10.1016/
S1470-2045(15)00188-6
See Online/Comment
http://dx.doi.org/10.1016/
S1470-2045(15)00224-7
Department of Medical
Oncology, Institut Curie, Paris
& Saint-Cloud, France
(C Le Tourneau MD);
Department of Medical
Oncology, Institut Claudius
Régaud, Toulouse, France
(Prof J-P Delord MD);
Department of Medical
Oncology, Institut Paoli-
Calmettes, Marseille, France
(Prof A Gonçalves MD);
Department of Medical
Oncology, Centre Alexis
Vautrin, Nancy, France
(C Gavoille MD); Department of
Medical Oncology, Institut
Curie, Saint-Cloud, France
(C Dubot MD); Department of
Medical Oncology, Centre
Georges-François Leclerc,
Dijon, France (N Isambert MD);
Department of Medical
Oncology (Prof M Campone MD)
and Genomic Unit
(P Jezequel MD), Centre René
Gauducheau, Nantes, France;
Department of Medical
Oncology (O Trédan MD) and
Genomic Unit (V Attignon PhD,
S Boyault PhD), Centre Léon
Bérard, Lyon, France;
Department of Pneumology,
Hopital Foch, Suresnes, France
(M-A Massiani MD);
Department of Biostatistics
(C Mauborgne MSc,
X Paoletti PhD), Clinical Trial
Management Unit
(S Armanet MSc),
Pharmacogenomics Unit
(I Bièche PhD), Translational
Research Department
(D Gentien PhD), NGS Platform
(V Bernard PhD), Department of
Medical Oncoology,
Molecularly targeted therapy based on tumour molecular
profi ling versus conventional therapy for advanced cancer
(SHIVA): a multicentre, open-label, proof-of-concept,
randomised, controlled phase 2 trial
Christophe Le Tourneau, Jean-Pierre Delord, Anthony Gonçalves, Céline Gavoille, Coraline Dubot, Nicolas Isambert, Mario Campone, Olivier Trédan,
Marie-Ange Massiani, Cécile Mauborgne, Sebastien Armanet, Nicolas Servant, Ivan Bièche, Virginie Bernard, David Gentien, Pascal Jezequel,
Valéry Attignon, Sandrine Boyault, Anne Vincent-Salomon, Vincent Servois, Marie-Paule Sablin, Maud Kamal, Xavier Paoletti, for the SHIVA investigators
Summary
Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours
harbour the matching molecular alteration. These results have led to increased off -label use of molecularly targeted
agents on the basis of identifi ed molecular alterations. We assessed the effi cacy of several molecularly targeted agents
marketed in France, which were chosen on the basis of tumour molecular profi ling but used outside their indications,
in patients with advanced cancer for whom standard-of-care therapy had failed.
Methods The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We
included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an
Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection
of a metastatic site, and at least one measurable lesion. The molecular profi le of each patient’s tumour was established
with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a
molecular alteration was identifi ed within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR,
RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib,
lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen).
We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or
treatment at physician’s choice (control group) by central block randomisation (blocks of size six). Randomisation was
done centrally with a web-based response system and was stratifi ed according to the Royal Marsden Hospital prognostic
score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment
allocation. Treatments in both groups were given in accordance with the approved product information and standard
practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint
was progression-free survival in the intention-to-treat population, which was not assessed by independent central
review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is
registered with ClinicalTrials.gov, number NCT01771458.
Findings Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients
had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff , Jan 20,
2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group.
All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control
group received a molecularly targeted agent: both were included in their assigned group for effi cacy analyses, the
patient who received an agent that was allowed in the experimental group was included in the experimental group for
the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy,
was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8–11·6) in the
experimental group and 11·3 months (8·1–11·6) in the control group at the time of the primary analysis of progression-
free survival. Median progression-free survival was 2·3 months (95% CI 1·7–3·8) in the experimental group versus
2·0 months (1·8–2·1) in the control group (hazard ratio 0·88, 95% CI 0·65–1·19, p=0·41). In the safety population,
43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic
chemotherapy had grade 3–4 adverse events (p=0·30).
Interpretation The use of molecularly targeted agents outside their indications does not improve progression-free
survival compared with treatment at physician’s choice in heavily pretreated patients with cancer. Off -label use of
molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess
predictive biomarkers of effi cacy.
Funding Institut Curie.
Articles
2
www.thelancet.com/oncology Published online September 3, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00188-6
(M Kamal PhD, M-P Sablin MD)
Department of Biopathology
(A Vincent-Salomon MD) and
Department of Radiology
(V Servois MD), Institut Curie,
Paris, France; Unité INSERM
U900, Paris, France
(N Servant PhD, X Paoletti); and
EA7285: Risques cliniques et
sécurité en santé des femmes
et en santé périnatale,
Versailles Saint-Quentin-en
Yvelines University,
Montigny-le-Bretonneux,
France (C Le Tourneau)
Correspondence to:
Dr Christophe Le Tourneau,
Department of Medical Oncology,
Institut Curie, 92210 Saint-Cloud,
France
Christophe.LeTourneau@curie.fr
Introduction
Normal cells become cancer cells via a succession of
genomic alterations.1 This fi nding has led to the
development of molecularly targeted agents that inhibit the
proteins that are abnormally activated as a result of somatic
genetic alterations. Theoretically, these agents are more
specifi c to cancer cells than are cytotoxic agents that target
cell replication. Some of these molecularly targeted agents
have yielded previously unprecedented anti-tumour activity
in specifi c tumour types in the presence of the matching
molecular alteration.2–7 Molecularly targeted agents have
followed the same clinical development process as cytotoxic
agents: per tumour location and histology. Most genetic
molecular alterations exist across tumour types and
histologies, although incidence varies.8 This observation
challenges the existing drug development strategies for
molecularly targeted agents and raises the possibility of a
shift towards histology-agnostic molecularly based
treatment with these drugs.
Advances in high-throughput technology have allowed
the identifi cation of multiple genomic molecular
alterations in a timeframe compatible with clinical
practice. The use of these technologies has been endorsed
by physicians and patients with the aim of guiding
therapy.9,10 This histology-agnostic approach is supported
by non-randomised studies. Using each patient as their
own control, a pilot study11 reported that 27% of patients
with any kind of recurrent cancer had a 30% increase in
progression-free survival with treatment selected on the
basis of tumour molecular profi ling compared with
progression-free survival for their previous treatment.
Similarly, fi ndings from a retrospective study12 showed
improved progression-free survival and overall survival
for cancer patients entering a phase 1 trial on the basis of
a molecular alteration identifi ed in their tumour.12 These
results, together with the decreasing cost of genomic
testing, have led to increased off -label use of molecularly
targeted agents.13
However, in view of the absence of data from
randomised trials, the clinical usefulness of large-scale
genomic testing has not been formally shown. In the
SHIVA trial, we aimed to assess whether histology-
agnostic use of marketed molecularly targeted agents
outside their indications based on tumour molecular
profi ling could improve outcomes for patients with any
kind of cancer for whom standard of care had failed,
compared with treatment at the physician’s choice.
Methods
Study design and participants
SHIVA was a proof-of-concept, multicentre, open-label,
randomised, controlled phase 2 trial of molecularly
targeted agents based on tumour molecular profi ling
versus treatment at physician’s choice in patients with
refractory cancer. The study was done at eight academic
sites in France (appendix 1 p 2).
Patients older than 18 years with any kind of recurrent
or metastatic solid tumour for whom standard of care
Research in context
Evidence before this study
At the start of our study in 2012, no evidence existed about
whether marketed molecularly targeted agents for cancer
should be given outside their indications in a histology-
agnostic way provided their target is altered. We searched
PubMed and ClinicalTrials.gov without any date restrictions and
congress abstracts from the yearly meetings of the American
Society of Clinical Oncology (ASCO) between 2000 and 2011 for
the terms “personalised medicine”, “clinical trials”, “high-
throughput technologies”, and “sequencing”. We used no
language restrictions. We identifi ed two non-randomised
studies. Using each patient as their own control, a pilot study
reported that 27% of patients with any type of recurrent cancer
had a 30% longer progression-free survival with treatment
selected on the basis of tumour molecular profi ling than they
did with their previous treatment. A retrospective study
similarly showed improved progression-free survival and overall
survival for cancer patients who entered a phase 1 trial on the
basis of a molecular alteration identifi ed on their tumour. We
postulated that the histology-agnostic use of marketed
molecularly targeted agents outside their indications on the
basis of tumour molecular profi ling would improve outcomes
for patients with any kind of cancer for whom standard of care
had failed, compared with treatment at the physician’s choice.
Added value of this study
Our study is, to the best of our knowledge, the fi rst comparative
randomised trial to assess a personalised approach in which
patients are treated with molecularly targeted agents in a
histology-agnostic way based on tumour molecular profi ling.
We found no signifi cant diff erence in progression-free survival
between molecularly targeted agents compared with treatment
at physician’s choice. We also noted more grade 3–4 adverse
events in the experimental group than in the control group.
Implications of all the available evidence
The generalisability of the treatment strategy chosen in SHIVA
to other strategies is limited by the fact that the results
depended on the drugs, profi ling assays, treatment
algorithms, and histology used. So far, no evidence from
randomised clinical trial supports the use of molecularly
targeted agents outside their indications on the basis of
tumour molecular profi ling. Our fi ndings suggest that off -label
use of molecularly targeted agents should be discouraged, and
enrolment into clinical trials encouraged. Despite a negative
result, our data suggest that further investigation of this
histology-agnostic approach is warranted in patients whose
tumours harbour a molecular alteration in the RAF/MEK
signalling pathway.
See Online for appendices
Articles
www.thelancet.com/oncology Published online September 3, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00188-6
3
therapy had failed were eligible for the study, provided
their disease was accessible for a biopsy or resection of a
metastatic site. We deemed standard of care to include
all treatments that have been reported to improve
survival or quality of life in randomised trials. To be
included, patients needed to have progressed on all
molecularly targeted agents approved for their disease
(except if contraindicated). Bone tumour sampling was
not allowed. Patients were allowed to receive a cytotoxic
agent, but no molecularly targeted agent or hormone
therapy, between the time of the biopsy and
randomisation. Patients needed to have an Eastern
Cooperative Oncology Group (ECOG) performance
status of 0 or 1; measurable disease in accordance with
Response Evaluation Criteria in Solid Tumors (RECIST)
version 1.1; and values within the prespecifi ed range for
absolute neutrophil count (≥1 × 10⁹ platelets per L),
platelets (≥1 × 10¹¹ cells per L), haemoglobin (≥90 g/L),
serum creatinine (≤1·5 times upper limit of normal
[ULN]), serum total bilirubin (≤1·5 times ULN), and
aspartate and alanine aminotransferases (≤3 times ULN
or ≤5 times ULN for patients with liver metastases).
Patients with brain metastases that had been controlled
for at least 3 months were eligible. We excluded patients
treated with anti-vitamin K anti coagulation. To be
eligible for randomisation, patients needed a left
ventricular ejection fraction more than 50%, a QTc
interval less than 480 ms, and preserved ECOG
performance status and renal, hepatic, and bone marrow
function. All patients provided written informed
consent.
We established molecular profi les for patient tumours
based on samples from a mandatory biopsy or resection
of a metastasis (appendix 1 pp 4–6). Molecular analyses
included assessment of mutations by targeted next
generation sequencing (AmpliSeq cancer panel on an
Ion Torrent/PGM system, Life Technologies, Carlsbad,
CA, USA; appendix 2); gene copy number alterations by
Cytoscan HD (Aff ymetrix, Santa Clara, CA, USA); and
expression of oestrogen, progesterone, and androgen
receptors by immunohistochemistry (appendix 1 p 4).
Patients were eligible for randomisation if one or several
molecular alterations were identifi ed that matched one of
the available molecularly targeted regimens.
The study was approved by the Ile-de-France ethics
committee. The trial was done in accordance with the
Declaration of Helsinki, the Good Clinical Practice
guidelines of the International Conference on
Harmonization, and relevant French and European laws
and directives. The study protocol is available in
appendix 1 (pp 16–298).
Randomisation and masking
We randomly assigned patients in a 1:1 ratio to receive
treatment with molecularly targeted agents or treatment
at physician’s choice. To control for patient heterogeneity,
randomisation was stratifi ed by three altered signalling
pathways (the hormone receptors pathway, the PI3K/
AKT/mTOR pathway, and the RAF/MEK pathway) and
patients’ prognoses based on the Royal Marsden Hospital
(RMH) score, divided into two categories (0 or 1 vs 2 or
3).14 We did not stratify patients by histology. The
biostatistics department of the Institut Curie (Paris,
France) did the randomisation via the web software
ALEA version 2, using block permutation (blocks of size
six) within each stratum. Treatment allocation was not
masked because of all the treatment choices available to
the investigators in the control group.
Procedures
The molecularly targeted agents that were given to the
experimental group were drugs that are approved for
clinical use in France, but outside their indications.
Single molecularly targeted agents (erlotinib, sorafenib,
imatinib, dasatinib, vemurafenib, everolimus,
abiraterone, letrozole, tamoxifen) were selected in
accordance with a predefi ned treatment algorithm,
except for patients whose tumour harboured a mutation
or an amplifi cation in HER2, who were treated with the
combination of trastuzumab and lapatinib (appendix 1
p 8). In both the experimental and control groups,
treatments were given according to the approved product
information and standard practice protocols at each
institution and were continued until evidence of disease
progression. If tumours had several molecular
alterations, prioritisation was discussed by the Molecular
Biology Board (appendix 1 p 5) based on the following
criteria: fi
rst, if the patient’s tumour expressed both
androgen receptor and oestrogen receptor or
progesterone receptor, the hormone receptor with the
highest expression was taken into account; second, any
mutation, amplifi cation, or deletion was deemed to be of
greater importance than was hormone receptor
expression; and third, in cases with several mutations,
amplifi cations, or deletions, the board judged alterations
to direct targets of a molecularly targeted agent to be of
highest priority for the treatment decision—if two
molecular alterations that were both direct targets of one
of the available molecularly targeted agents were present,
the board would make the decision based on which
alteration was downstream.
A crossover was proposed at disease progression for
patients in both treatment groups. Quotas were introduced
so that no more than 20% of the randomly assigned
patients in each group had the same tumour type and
histology. The treating physician was only informed of the
result of the molecular alteration of interest at the time
when the patient was about to start treatment with the
matched molecularly targeted agent, whether this was at
randomisation or at crossover.
The criteria for removal of a patient from the study
were disease progression (after crossover, if any), death,
unacceptable toxic eff ects, patient’s decision, and
investigator’s choice. Tumour assessments were done
Articles
4
www.thelancet.com/oncology Published online September 3, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00188-6
Figure 1: Trial profi le
741 screened
716 underwent tumour sampling
638 immunohistochemistry 522 gene copy number analysed
7 quality control not met
515 passed quality control638 passed quality control
496 had complete profile
293 enrolled
195 randomly assigned to
treatment
25 tumour sampling not done
78 no tumour cells
112 insufficient tumour cellularity
3 insufficient DNA
1 tumour not frozen
78 no tumour cells
112 insufficient tumour cellularity
3 insufficient DNA
1 tumour not frozen
2 run failed
520 sequenced
13 quality control not met
507 passed quality control
70 randomisation criteria not met
22 deaths
3 consent withdrawal
3 lost to follow-up
78 no tumour cells
203 no targetable molecular alteration
99 assigned to molecularly targeted agent 96 assigned to treatment at physician’s choice
99 treated
8 treatment ongoing 2 treatment ongoing
99 included in intention-to-treat analysis 96 included in intention-to-treat analysis
92 treated
90 stopped treatment
79 progressive disease
57 deaths
1 patient lost to follow-up
3 lost for unknown reasons
91 stopped treatment
76 progressive disease
61 deaths
Articles
www.thelancet.com/oncology Published online September 3, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00188-6
5
before patients started the study treatment (baseline),
then every 8 weeks (plus or minus 1 week). Adverse
events, laboratory values, and vital signs were assessed in
accordance with the approved product information and
standard practice protocols at each institution throughout
the study.
Outcomes
The primary endpoint of the study was progression-free
survival, defi ned as the time from randomisation to
death from any cause or progression according to
RECIST 1.1.15 Secondary endpoints were safety and
proportion of patients with an objective response to
treatment as assessed by RECIST. Progression-free
survival and the proportion of patients with an objective
response were also assessed in patients who crossed
over, as were tumour growth kinetics for both
treatments.16 Outcomes were not centrally reviewed.
Adverse events were graded according to the National
Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE), version 4.03.
Statistical analysis
The objective of the study was to detect a diff erence in
progression-free survival between the treatment groups.
Expected 6-month progression-free survival in the
control group was 15%.17 We postulated that the
experimental group would have 40% longer progression-
free survival than that of the control group (hazard ratio
[HR] 0·625). A total of 142 events was needed to detect a
statistically signifi cant diff erence with a type I error rate
of 5% and a power of 80% in a two-sided setting. To be
able to see these events, we planned to include a total of
200 patients.
All analyses were done by the sponsor using data
obtained up to Jan 20, 2015. The primary analysis was
done in the intention-to-treat population. A log-rank
test was used in the primary analysis to evaluate
progression-free survival, with stratifi cation according
to the altered molecular pathway and patients’
prognoses (as measured by the RMH score). The
results are presented as Kaplan-Meier curves. HRs
were estimated with a stratifi ed Cox proportional
hazards model after a visual check of the underlying
assumptions. Interaction tests and subgroup analyses
were done to establish whether treatment eff ects were
consistent between patient subgroups. Safety analyses
were done according to the treatment received by all
patients who started treatment (molecularly targeted
agent alone vs cytotoxic chemotherapy with or without
molecularly target agent). All tests were two-sided at
the 5% signifi cance level. All statistical analyses were
done with SAS version 9.4.
An independent safety monitoring committee
supervised the collation of the safety data. This
trial is registered with ClinicalTrials.gov, number
NCT01771458.
Role of the funding source
The sponsor of the study was involved in the study
design, data collection, and data analysis. All authors had
full access to all the data in the study, made the decision
to submit these data for publication, were involved in
writing the manuscript, and agreed on the fi nal content
Molecularly
targeted agent
group (n=99)
Treatment at
physician’s
choice group
(n=96)
Age (years) 61 (54–69) 63 (54–69)
Sex
Female 60 (61%) 69 (72%)
Male 39 (39%) 27 (28%)
Previous lines of treatment 3 (2–5) 3 (2–5)
Royal Marsden Hospital score
0 or 1 51 (52%) 48 (50%)
2 or 3 48 (48%) 48 (50%)
Molecular pathway altered
Hormone receptor pathway 40 (40%) 42 (44%)
PI3K/AKT/mTOR pathway 46 (46%) 43 (45%)
RAF/MEK pathway 13 (13%) 11 (11%)
Tumour type
Breast adenocarcinoma 22 (22%) 18 (19%)
Ovarian cancer 12 (12%) 17 (18%)
Lung cancer 9 (9%) 10 (10%)
Colorectal cancer 9 (9%) 9 (9%)
Cervical cancer 12 (12%) 7 (7%)
Head and neck squamous cell
carcinoma
6 (6%) 5 (5%)
Sarcoma 4 (4%) 4 (4%)
Urothelial carcinoma 2 (2%) 4 (4%)
Pancreatic adenocarcinoma 3 (2%) 2 (2%)
Adenocarcinoma of unknown
primary
2 (2%) 3 (3%)
Oesophagogastric cancer 3 (3%) 2 (2%)
Adenoid cystic carcinoma 1 (1%) 3 (3%)
Non-adenoid cystic carcinoma
salivary gland tumour
2 (2%) 2 (2%)
Hepatocelular carcinoma 1 (1%) 2 (2%)
Anal squamous cell carcinoma 1 (1%) 2 (2%)
Neuroendocrine tumour 2 (2%) 1 (1%)
Biliary tract carcinoma 1 (1%) 1 (1%)
Nasopharyngeal carcinoma 1 (1%) 1 (1%)
Cutaneous melanoma 1 (1%) 1 (1%)
Mesothelioma 0 1 (1%)
Peritoneal tumour 0 1 (1%)
Ependymoma 1 (1%) 0
Prostate adenocarcinoma 1 (1%) 0
Uveal melanoma 1 (1%) 0
Germline tumour 1 (1%) 0
Kidney cancer 1 (1%) 0
Data are n (%), or median (IQR).
Table 1: Baseline characteristics
Articles
6
www.thelancet.com/oncology Published online September 3, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00188-6
of the paper. The corresponding author had fi nal
responsibility for the decision to submit for publication.
XP and CM had access to the raw data.
Results
Enrolment started on Oct 4, 2012, and stopped on July 11,
2014, after the inclusion of 741 patients in the screening
programme because a preliminary analysis suggested
that 200 of these patients would be suitable for inclusion.
A complete molecular profi le was available for 496 (67%)
patients (fi gure 1). A molecular alteration matching one
of the available molecularly targeted agents was detected
in 293 (40%) patients.
At the cutoff date (Jan 20, 2015), 195 (26%) of the
original 741 patients had been randomly assigned to
receive either a molecularly targeted agent (experimental
group, 99 patients) or treatment at the physician’s choice
(control group, 96 patients). Baseline characteristics were
similar between the two groups (table 1). Tumour types
seemed to be evenly distributed between the groups.
Median time from biopsy to randomisation was 65 days
(IQR 44–124) in the experimental group and 57 days
(42–94) in the control group.
Focusing only on molecular alterations of interest for
the trial and excluding oestrogen receptor and
progesterone receptor positivity in patients with breast
cancer (which was not taken into account in the treatment
algorithm, because hormone therapy is standard of care
for this disease), 55 (28%) of the 195 patients who were
assigned to one of the groups had two or more molecular
alterations of interest, and none had more than four
alterations. Of these 55 patients, fi ve had only oestrogen
receptor or progesterone receptor expression and nine
had molecular alterations aff ecting only the PI3K/AKT/
mTOR pathway, which, according to the treatment
algorithm, did not change the treatment assigned. Only
41 (21%) patients had at least two molecular alterations
that would potentially lead to diff erent choices of
molecularly targeted agents. Of these 41 patients,
26 expressed a hormone receptor and a molecular
alteration aff ecting the PI3K/AKT/mTOR pathway (in
which case everolimus was given), 14 had both androgen
receptor and oestrogen receptor or progesterone receptor
expression (in which case treatment was chosen based
on the most prevalent hormone receptor), and one
patient had a PDGFRA mutation (Leu655Trp) associated
with a PIK3CA mutation (Glu545Lys). The PDGFRA
mutation was judged to be more important because of
the availability of sorafenib, which is a direct inhibitor of
PDGFRA, as opposed to everolimus, which targets
mTOR downstream of PI3KCA.
82 patients had a molecular alteration aff ecting the
hormone receptor pathway, including 49 (60%) patients
who had androgen receptor expression and 33 (40%) who
had oestrogen receptor or progesterone receptor
expression. 89 patients had alterations in the PI3K/AKT/
mTOR pathway and 24 had alterations in the RAF/MEK
pathway (fi gure 2; appendix 1 p 14). Appendix 1 shows the
molecular alterations of interest according to tumour
types (pp 9–11). In addition to the molecular alterations
of interest for the trial, other molecular alterations
Figure 2: Distribution of molecular alterations in the PI3K/AKT/mTOR pathway (A) and RAF/MEK
pathway (B)
*PTEN inactivations included homozygous deletions and heterozygous deletions associated with inactivating
mutations or validated by absence of expression of PTEN in immunohistochemistry. †STK11 inactivations included
homozygous deletions and heterozygous deletions associated with inactivating mutations of STK11. ‡Focal gains
of several PIK3 pathway genes including AKT1, AKT2, AKT3, RPTOR, and RICTOR (three patients). §Intragenic
deletion within PDGFRA validated by overexpression of PDGFRA in immunohistochemistry. ¶Intragenic deletion
within KIT validated by overexpression of the KIT in immunohistochemistry.
52% 33%
7%
3%
1%
1%
2%
1%
PTEN inactivations*
STK11 inactivations†
Others‡
PIK3CA activating mutations
PIK3CA activating mutations associated with PTEN inactivation
PIK3CA activating mutations associated with STK11 inactivation
AKT1 amplifications
AKT1 activating mutations
LCK amplifications
PDGFRA amplifications
PDGFRA activating mutations
PDGFRA activation§
PDGFRB amplifications
KIT activating mutations
KIT activation¶
4%
4%
4%
4%4%
4%
8%
8%
13%
8%
4%
17%
17%
FLT3 activating mutations
RET amplifications
ERBB2 amplifications
ERBB2 activating mutations
EGFR amplifications
BRAF activating mutations
A
B
Figure 3: Progression-free survival
*One patient had a follow-up of zero days so is not shown here.
Number at risk
Molecularly
targeted agent
Treatment at
physician’s choice
024681012
99
95*
62
50
20
19
10
12
5
8
2
1
0
0
Time (months)
HR 0·88 (95% CI 0·65–1·19); p=0·41
0
20
40
60
80
100
Progression-free survival (%)
Molecularly targeted agent
Treatment at physician’s choice
Articles
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7
seemed to be well balanced between both arms. For
example, TP53 mutations were present in 42 (46%) of 91
patients with sequencing data in the experimental group
versus 34 (40%) of 84 patients in the control group.
Out of the 96 patients allocated to the control group,
92 actually started treatment (fi gure 1), including 70 (76%)
patients who received single-agent treatment, 19 (21%)
who received combination treatment, and three (3%)
who received best supportive care alone. Two patients in
the control group received a molecularly targeted agent:
one received erlotinib and the other received a
combination of eribulin and trastuzumab. The patient
who received erlotinib was included in the experimental
group for the purposes of safety analyses; the other
patient received a molecularly targeted agent and
cytotoxic chemotherapy and was analysed for safety in
the control group. Both patients were included in the
control group for effi cacy analyses. 63 patients crossed
over in the control group, and 21 in the experimental
group.
Median follow-up at the time of this analysis was
11·3 months (IQR 5·8–11·6) in the experimental group
and 11·3 months (8·1–11·6) in the control group. Median
progression-free survival was 2·3 months (95% CI
1·7–3·8) in the experimental group versus 2·0 months
(1·8–2·1) in the control group (HR 0·88, 95% CI
0·65–1·19, p=0·41; fi gure 3). Progression-free survival at
6 months was 13% (95% CI 7–20) in the control group
and 11% (6–19) in the experimental group. Objective
responses were noted in four (4·1%, 95% CI 0·0–8·0) of
98 assessable patients in the experimental group and
three (3·4%, 1·0–9·5) of 89 assessable patients in the
control group (p=0·19).
We detected no interaction between the altered
molecular pathway and treatment eff
ect (p=0·49). In the
hormone receptor pathway subgroup, median
progression-free survival was 2·1 months (95% CI
1·8–2·5) in the experimental group versus 2·0 months
(1·7–2·7) in the control group (HR 1·12, 95% CI
0·70–1·78, p=0·64; fi gure 4A). In the PI3K/AKT/mTOR
pathway subgroup, median progression-free survival was
2·4 months (1·9–3·3) in the experimental group versus
1·9 months (1·7–2·0) in the control group (HR 0·79,
95% CI 0·51–1·24, p=0·30; fi gure 4B). In the RAF/MEK
pathway subgroup, median progression-free survival was
3·7 months (1·3–5·6) in the experimental group versus
2·0 months (1·0–2·9) in the control group (HR 0·58,
95% CI 0·24–1·37, p=0·20; fi gure 4C). In the subgroup
of patients with an RMH score of 2 or 3, the HR was
1·0 (95% CI 0·69–1·42, p=0·99) for the experimental
versus control groups. For patients with an RMH score
of 0 or 1, the HR was 0·74 (95% CI 0·51–1·07, p=0·12).
Within the safety population, grade 3–4 adverse events
were noted for 43 (43%) of the 100 patients who received a
molecularly targeted agent (including 99 patients from the
experimental group and the patient in the control group
who received erlotinib) and 32 (35%) of the 91 patients
Figure 4: Progression-free survival by molecular pathway
Progression-free survival in patients with molecular alterations in the hormone receptor pathway (A), PI3K/AKT/
mTOR pathway (B), and RAF/MEK pathway (C).
Number at risk
Molecularly
targeted agent
Treatment at
physician’s choice
40
41
24
24
5
10
4
6
2
5
2
1
0
0
HR 1·12 (95% CI 0·70–1·78); p=0·64
0
20
40
60
80
100
Progression-free survival (%)
Molecularly targeted agent
Treatment at physician’s choice
Number at risk
Molecularly
targeted agent
Treatment at
physician’s choice
46
43
29
19
9
7
3
5
1
2
0
0
HR 0·79 (95% CI 0·51–1·24); p=0·30
0
20
40
60
80
100
Progression-free survival (%)
Number at risk
Molecularly
targeted agent
Treatment at
physician’s choice
024681012
13
11
9
7
6
2
3
1
2
1
0
0
Time (months)
HR 0·58 (95% CI 0·24–1·37); p=0·20
0
20
40
60
80
100
Progression-free survival (%)
A
B
C
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who received cytotoxic chemotherapy (p=0·30; table 2).
Treatment interruptions or dose delays were reported for
30 (30%) of the patients given a molecularly targeted
agent, and 16 (18%) of the patients given cytotoxic
chemotherapy. No deaths related to study drugs occurred
during the trial.
Grade 3–4 adverse events were reported for 14 (34%) of
the 41 patients who received hormone therapy, 23 (50%) of
the 46 patients treated with everolimus, and six (46%) of
the 13 patients treated with the remaining molecularly
targeted agents. In the patients who received chemotherapy,
grade 3–4 adverse events were reported for 13 (27%) of the
48 patients with an RMH score of 0 or 1, and 19 (44%) of
the 43 patients with an RMH score of 2 or 3. In the patients
who received molecularly targeted agents, grade 3–4
adverse events were reported for 23 (45%) of the 51 patients
with an RMH score of 0 or 1, and 20 (41%) of the 49 patients
with an RMH score of 2 or 3.
Discussion
The SHIVA trial is a histology-agnostic randomised trial
that has many features in common with the proposed
expansion platform type IIB design.18 Patient accrual
went twice as fast as anticipated, which shows the
enthusiasm that patients and physicians have for trials
that use molecular information to guide therapy.9,10,19
Our fi ndings indicate that the use of molecularly
targeted agents outside their indications does not
improve progression-free survival compared with
treatment at physician’s choice in heavily pretreated
patients with cancer.
The success rate of our genomic analyses was similar
to those reported in other trials that use large-scale
genomic testing on samples from metastases, with the
main reason for failure being low cellularity.19–21 The 40%
prevalence of patients with a molecular alteration that
could be targeted with drugs according to our predefi ned
treatment algorithm is in line with those reported
previously.12,19–21 Conversely, the proportion of patients
screened (26%) who reached the randomisation stage is
higher than in other histology-agnostic studies, probably
because treatment was part of the study and did not
depend on available clinical trials.20,21 The need for fresh
frozen biopsies and real-time molecular analyses was
Patients who received molecularly targeted agents
(n=100*)
Patients who received cytotoxic chemotherapy (n=91†)
Grade 2 necessitating drug
interruption or delay‡
Grade 3 Grade 4 Grade 2 necessitating drug
interruption or delay
Grade 3 Grade 4
Any event§ 12 (12%) 36 (36%) 7 (7%) 9 (10%) 28 (31%) 4 (4%)
Neutropenia 0 1 (1%) 0 0 5 (5%) 2 (2%)
Febrile neutropenia 0 1 (1%) 0 0 0 0
Anaemia 0 5 (5%) 0 2 (2%) 4 (4%) 0
Thrombocytopenia 1 (1%) 1 (1%) 1 (1%) 0 0 1 (1%)
Loss of appetite 2 (2%) 0 1 (1%) 0 2 (2%) 0
Asthenia 0 2 (2%) 3 (3%) 2 (2%) 2 (2%) 0
Nausea 2 (2%) 2 (2%) 0 1 (1%) 0 0
Vomiting 0 1 (1%) 0 0 0 0
Mucositis 0 1 (1%) 0 0 1 (1%) 0
Constipation 0 0 0 0 1 (1%) 0
Abdominal pain 0 1 (1%) 0 0 0 0
Weight loss 1 (1%) 0 0 0 0 0
Weight gain 0 0 0 1 (1%) 0 0
Dyspnoea 1 (1%) 6 (6%) 0 0 2 (2%) 0
Skin reactions 1 (1%) 1 (1%) 0 0 0 0
Cardiac ischaemia 0 0 0 0 1 (1%) 0
Arrhythmia 0 0 0 0 1 (1%) 0
Arthralgia 0 2 (2%) 0 0 0 0
Peripheral neuropathy 0 1 (1%) 0 0 1 (1%) 0
Aspartate aminotransferase increase 0 2 (2%) 0 0 0 0
Creatinine increase 0 0 0 0 1 (1%) 0
Other 2 (2%) 9 (9%) 5 (5%) 3 (3%) 6 (7%) 1 (1%)
*Includes one patient allocated to the control group who received a molecularly targeted agent that was permitted in the experimental group. †Four patients in the control
group never started treatment and one patient received a molecularly targeted agent that was permitted in the experimental group. ‡Only grade 2 adverse events that led to
a treatment interruption or a dose delay were recorded, whereas all grade 3–5 adverse events were recorded. §For any adverse events, only the adverse event with the worst
grade was reported.
Table 2: Adverse events
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9
challenging for the eight academic centres involved in
the trial.22 Although use of such approaches is not yet
widespread, technological advances in next generation
sequencing methods and circulating tumour DNA
analysis will allow these limitations to be overcome in the
future.23
The main aim of the trial was to assess whether use of
molecularly targeted agents outside their indications
improved patient outcomes if given on the basis of
identifi ed molecular alterations according to a predefi ned
treatment algorithm. The treatment algorithm, which
describes how potential molecular alterations can be
matched to molecularly targeted agents, was extensively
discussed before we started the trial and fi xed thereafter
to ensure reproducibility and homogeneous interpretation
of molecular alterations between patients. In the trial, we
assessed molecularly targeted agents that are marketed in
France and have either a clinically validated biomarker in
another indication, such as HER2 amplifi cation for the
trastuzumab and lapatinib combination, or biomarkers
supported by preclinical data, such as a PTEN loss for
everolimus. The treatment algorithm is one of the key
elements being assessed in this trial, because the study
was not powered to conclude whether one of the
molecularly targeted agents used is eff ective for any
molecularly or histologically characterised subgroup of
patients. The trial failed to show the prespecifi ed 15–30%
improvement in progression-free survival at 6 months,
but a smaller true benefi t might not have been detected
because of insuffi
cient power. Moreover, there was
insuffi cient power to detect such a diff erence in the
subset of patients with genomic alterations (n=113) only,
excluding patients with hormonal molecular alterations.
Overall, the adverse event profi le was consistent with
previous reports. However, severe adverse events (ie,
grades 3–4), whether related to study drugs or not, were
more common with molecularly targeted agents than
with chemotherapy, as were treatment interruptions or
delays, although this diff erence was not signifi cant. This
result is counterintuitive, especially in view of the fact
that almost half of patients in the experimental group
were treated with hormone therapy, which is supposed to
produce very few severe adverse events. Associations
between adverse events and the individual study drugs
were not taken into account in our study, which might
explain the high numbers of severe adverse events seen.
Nevertheless, the increased prevalence in patients who
received molecularly targeted agents emphasises the fact
that the safety profi les of these drugs might not be
favourable in heavily pretreated patients compared with
conventional chemotherapy.
The proportion of patients with an objective response
and progression-free survival in the control group of the
trial was similar to those reported for other heavily
pretreated patients included in early phase clinical trials
without molecular selection.12,17,21 Overall survival and
crossover data were not mature at the cutoff date and will
be reported later. The proportions of patients with an
objective response and progression-free survival were
not signifi cantly diff erent between the experimental
group and control group, and therefore do not support
the favourable results obtained in non-randomised
studies in which patients received a molecularly targeted
agent matching an identifi ed molecular alteration.11,12,21
However, the diff erence in progression-free survival in
the subgroup of patients who received drugs targeting
the RAF/MEK pathway in the experimental group was
similar to the improvement in progression-free survival
reported by these studies, although patients in those
studies were often treated with drug combinations.11,12,21
In this subgroup of patients with alterations in the RAF/
MEK pathway, the HR was 0·58, although it was not
signifi cant, possibly because of the small number of
patients. The overall result of our study was possibly
negatively aff ected by the drugs targeting hormone
receptors (HR 1·12) and everolimus used for the PI3K/
AKT/mTOR pathway (HR 0·79), which is now known
not to be the best molecularly targeted agent to target
molecular alterations at diff erent levels of this pathway.
The RMH prognostic score predicts survival in heavily
pretreated patients with cancer and is often used to select
patients for phase 1 clinical trials.14 Our study suggests
that only patients whose RMH score predicts a longer life
expectancy would potentially benefi t from our histology-
agnostic approach, although the diff erence between
RMH groupings was not signifi cant. This absence of a
signifi cant diff erence might be related to the fact that
molecularly targeted agents are known to need some
time to produce anti-tumour eff ects. Patients with a poor
prognosis might deteriorate before they have received
enough exposure to molecularly targeted agents.
Several key points might explain the overall negative
result of the SHIVA trial. First, we acknowledge that our
use of multiple treatment groups composed of many
molecular alterations in patients with various tumour
types and histologies introduced an important source of
variability into the analysis. The treatment algorithm
used in our trial was unidimensional, with single
molecular alterations supposed to predict the effi cacy of
molecularly targeted agents. Preliminary data suggest
that information on coexisting molecular alterations
might help to predict the effi cacy of molecularly targeted
agents. For example, PI3K inhibitors have been reported
to be eff ective in some patients with tumours harbouring
a PI3KCA mutation, while coexisting PI3KCA and KRAS
mutations have been reported to predict the reduced
effi cacy of PI3K inhibitors.24 Whether multidimensional
treatment algorithms that incorporate information from
several genes using systems biology approaches will be
able to better predict response to molecularly targeted
agents remains to be established. Second, the molecularly
targeted agents were mostly used as single agents in our
study, which often led to reduced effi cacy through the
development of resistance. Use of several molecularly
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targeted agents in combination is an appealing way to
counteract resistance. For example, the combination of a
BRAF inhibitor and a MEK inhibitor has been shown to
be more eff ective than a BRAF inhibitor as a single agent
in Val600Glu BRAF-mutated recurrent or metastatic
melanoma.25 Although use of drug combinations is
appealing, they are associated with safety concerns.26
Third, spatial and temporal intrapatient heterogeneity
was not taken into consideration in our study.
Improvements in molecular analyses of circulating
tumour DNA might allow tumour evolution to be
readdressed over time and therapy potentially revised
accordingly. Fourth, the only available molecularly
targeted agents in our study were those that were
marketed in France, which might not be the best drugs
for a given molecular alteration. As an example, dual
mTORC inhibitors might be more appropriate than
everolimus to target the PI3K/AKT/mTOR pathway.
Additionally, the small number of molecularly targeted
agents available in this study did not cover the whole
range of actionable oncogenic drivers. Finally, our study
included heavily pretreated patients, which reduced the
likelihood that molecularly targeted agents will be
eff ective. Targeting of HER2 with trastuzumab, for
example, decreases the recurrence risk by half in the
adjuvant setting in HER2-overexpressing breast cancer,27
but only reduces death by 20% in the metastatic setting.28
The generalisability of the treatment strategy chosen in
SHIVA to other strategies is restricted by the fact that the
results depend on the drugs, profi ling assays, treatment
algorithms, and histology used. However, our results
showed no statistically signifi cant diff erence in
progression-free survival between the molecularly targeted
agent and treatment at physician’s choice groups in
heavily pretreated patients. Our fi ndings suggest that off -
label use of molecularly targeted agents should be
discouraged, and enrolment into clinical trials should be
encouraged to help identify predictive biomarkers of
effi cacy. Our results emphasise the need to, fi rst, discover
more eff ective molecularly targeted agents; second, extend
and refi ne treatment algorithms so they take potential
drug combinations into account to avoid resistance; and
third, investigate this approach at an earlier disease stage.
Further investigation of this histology-agnostic approach
pathway is warranted for patients with molecular
alterations in the RAF/MEK pathway. Future clinical trials
should be encouraged to address in their designs the
challenge of spatial and temporal intrapatient tumour
heterogeneity to identify the most representative patient
sample to guide therapy according to the relevant
molecular alteration of the patient’s disease.
Contributors
The primary data were made available to the investigators for
independent central review and analyses. CLT wrote the fi rst draft of the
manuscript, with review and revision by the other authors. All authors
had full access to all the data in the study, made the decision to submit
these data for publication, were involved in writing the manuscript, and
agreed on the fi nal content of the manuscript.
Declaration of interests
MC reports grants from Novartis, AstraZeneca, Roche, Menarini, and
Sanofi . All other authors declare no competing interests.
Acknowledgments
We thank the patients who volunteered to participate in this study for
their dedication and the study-site staff who cared for them. This work
is supported by grant ANR-10-EQPX-03 from the Agence Nationale de
le Recherche (Investissements d’avenir) and Site de Recherche Intégré
contre le Cancer (SiRIC). High-throughput sequencing was done by
the NGS platform of the Institut Curie, supported by grants ANR-10-
EQPX-03 and ANR-10-INBS-09-08 from the Agence Nationale de le
Recherche (investissements d’avenir) and the Canceropôle Ile-de-
France.
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